tbuckley/cabot-search huggingface dataset:
Reproducible changes in the anorexia nervosa gut microbiota following inpatient therapy remain distinct from non-eating disorder controls
Authors: Farnaz Fouladi, Emily C. Bulik-Sullivan, Elaine M. Glenny, Laura M. Thornton, Kylie K. Reed, Stephanie Thomas, Susan Kleiman, Ashlie Watters, Judy Oakes, Eun-Young Huh, Quyen Tang, Jintong Liu, Zorka Djukic, Lauren Harper, Yesel Trillo-Ordoñez, Shan Sun, Ivory Blakely, Philip S. Mehler, Anthony A. Fodor, Lisa M. Tarantino, Cynthia M. Bulik, Ian M. Carroll
Journal: Gut Microbes (2022)

The composition of the gut microbiota in patients with anorexia nervosa (AN), and the ability of this microbial community to influence the host, remains uncertain. To achieve a broader understanding of the role of the intestinal microbiota in patients with AN, we collected fecal samples before and following clinical treatment at two geographically distinct eating disorder units (Center of Excellence for Eating Disorders [UNC-CH] and ACUTE Center for Eating Disorders [Denver Health]). Gut microbiotas were characterized in patients with AN, before and after inpatient treatment, and in non-eating disorder (non-ED) controls using shotgun metagenomic sequencing. The impact of inpatient treatment on the AN gut microbiota was remarkably consistent between eating disorder units. Although weight in patients with AN showed improvements, AN microbiotas post-treatment remained distinct from non-ED controls. Additionally, AN gut microbiotas prior to treatment exhibited more fermentation pathways and a lower ability to degrade carbohydrates than non-ED controls. As the intestinal microbiota can influence nutrient metabolism, our data highlight the complex microbial communities in patients with AN as an element needing further attention post inpatient treatment. Additionally, this study defines the effects of renourishment on the AN gut microbiota and serves as a platform to develop precision nutrition approaches to potentially mitigate impediments to recovery.
Gut microbiota composition as a candidate risk factor for dimethyl fumarate-induced lymphopenia in multiple sclerosis
Authors: Martin Diebold, Marco Meola, Srinithi Purushothaman, Lena K Siewert, Elisabeth Pössnecker, Tim Roloff, Raija LP Lindberg, Jens Kuhle, Ludwig Kappos, Tobias Derfuss, Adrian Egli, Anne-Katrin Pröbstel
Journal: Gut Microbes (2022)

Mounting evidence points towards a pivotal role of gut microbiota in multiple sclerosis (MS) pathophysiology. Yet, whether disease-modifying treatments alter microbiota composition and whether microbiota shape treatment response and side-effects remain unclear. In this prospective observational pilot study, we assessed the effect of dimethyl fumarate (DMF) on gut microbiota and on host/microbial metabolomics in a cohort of 20 MS patients. Combining state-of-the-art microbial sequencing, metabolome mass spectrometry, and computational analysis, we identified longitudinal changes in gut microbiota composition under DMF-treatment and an increase in citric acid cycle metabolites. Notably, DMF-induced lymphopenia, a clinically relevant safety concern, was correlated with distinct baseline microbiome signatures in MS patients. We identified gastrointestinal microbiota as a key therapeutic target for metabolic properties of DMF. By characterizing gut microbial composition as a candidate risk factor for DMF-induced lymphopenia, we provide novel insights into the role of microbiota in mediating clinical side-effects.
Succinic Ester‐Based Shape Memory Gelatin Sponge for Noncompressible Hemorrhage without Hindering Tissue Regeneration
Authors: Ye Zhu, Lining Zhang, Wanglin Duan, Sergio Martin‐Saldaña, Chaowei Li, Hongwen Yu, Luyao Feng, Xianpeng Zhang, Baoji Du, Guanying Li, Xifu Zheng, Yazhong Bu
Journal: Advanced Healthcare Materials (2022)

Abstract Shape memory sponges are very promising in stopping the bleeding from noncompressible and narrow entrance wounds. However, few shape memory sponges have fast degradable properties in order to not hinder tissue healing. In this work, based on cryopolymerization, a succinic ester‐based sponge (Ssponge) is fabricated using gelatin and bi‐polyethylene glycol‐succinimidyl succinate (Bi‐PEG‐SS). Compared with the commercially available gelatin sponge (Csponge), Ssponge possesses better water/blood absorption ability and higher mechanical pressure over the surrounding tissues. Moreover, in the models of massive liver hemorrhage after transection and noncompressive liver wounds by penetration, Ssponge exhibits a better hemostasis performance than Csponge. Furthermore, in a liver regeneration model, Ssponge‐treated livers shows higher regeneration speed compared with Csponge, including a lower injury score, more cavity‐like tissues, less fibrosis and enhanced tissue regeneration. Overall, it is shown that Ssponge, with a fast degradation behavior, is not only highly efficient in stopping bleeding but also not detrimental for tissue healing, possessing promising clinical translational potential.
Risk-Adapted Starting Age for Personalized Colorectal Cancer Screening: Validated Evidence From National Population-Based Studies
Authors: Xuesi Dong, Zilin Luo, Zheng Wu, Dong Hang, Changfa Xia, Fei Wang, Yadi Zheng, Yiwen Yu, Yongjie Xu, Wei Cao, Chao Qin, Liang Zhao, Jiang Li, Jiansong Ren, Jufang Shi, Mulong Du, Wanqing Chen, Hongbing Shen, Ni Li, Jie He
Journal: Clinical Gastroenterology and Hepatology (2022)
Friend turned foe: TREM2 agonist in battles against tau
Authors: Gillian Carling, Wenjie Luo, Li Gan
Journal: The Journal of Experimental Medicine (2022)

In this important study, Jain et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20220654) find that chronic TREM2 activation by AL002a antibody exacerbates the seeding and spread of pathological tau, enhances the disease-associated microglial signature, and increases neurite dystrophy in 5xFAD mice seeded with Alzheimer's disease tau.
Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease
Authors: George Cholankeril, Jennifer R. Kramer, Jinna Chu, Xian Yu, Maya Balakrishnan, Liang Li, Hashem B. El-Serag, Fasiha Kanwal
Journal: Journal of Hepatology (2022)
Don’t turn away—a book not just to be read, but to be acted on
Authors: Iona Heath
Journal: BMJ (2022)

A Fortunate Man, Dr Sassall says: "All diffidence in my position is a fault.A form of negligence." 1 Diffidence is perhaps the least culpable manifestation of turning away, but it remains a kind of dismissal and a failure to pay attention to the detail of another's distress.
OXPHOS promotes apoptotic resistance and cellular persistence in T <sub>H</sub> 17 cells in the periphery and tumor microenvironment
Authors: Hanna S. Hong, Nneka E. Mbah, Mengrou Shan, Kristen Loesel, Lin Lin, Peter Sajjakulnukit, Luis O. Correa, Anthony Andren, Jason Lin, Atsushi Hayashi, Brian Magnuson, Judy Chen, Zhaoheng Li, Yuying Xie, Li Zhang, Daniel R. Goldstein, Shannon A. Carty, Yu Leo Lei, Anthony W. Opipari, Rafael J. Argüello, Ilona Kryczek, Nobuhiko Kamada, Weiping Zou, Luigi Franchi, Costas A. Lyssiotis
Journal: Science Immunology (2022)

T cell proliferation and cytokine production are bioenergetically and biosynthetically costly. The inability to meet these metabolic demands results in altered differentiation, accompanied by impaired effector function, and attrition of the immune response. Interleukin-17–producing CD4 T cells (T H 17s) are mediators of host defense, autoimmunity, and antitumor immunity in the setting of adoptive T cell therapy. T H 17s are long-lived cells that require mitochondrial oxidative phosphorylation (OXPHOS) for effector function in vivo. Considering that T H 17s polarized under standardized culture conditions are predominately glycolytic, little is known about how OXPHOS regulates T H 17 processes, such as their ability to persist and thus contribute to protracted immune responses. Here, we modified standardized culture medium and identified a culture system that reliably induces OXPHOS dependence in T H 17s. We found that T H 17s cultured under OXPHOS conditions metabolically resembled their in vivo counterparts, whereas glycolytic cultures were dissimilar. OXPHOS T H 17s exhibited increased mitochondrial fitness, glutamine anaplerosis, and an antiapoptotic phenotype marked by high BCL-XL and low BIM. Limited mitophagy, mediated by mitochondrial fusion regulator OPA-1, was critical to apoptotic resistance in OXPHOS T H 17s. By contrast, glycolytic T H 17s exhibited more mitophagy and an imbalance in BCL-XL to BIM, thereby priming them for apoptosis. In addition, through adoptive transfer experiments, we demonstrated that OXPHOS protected T H 17s from apoptosis while enhancing their persistence in the periphery and tumor microenvironment in a murine model of melanoma. Together, our work demonstrates how metabolism regulates T H 17 cell fate and highlights the potential for therapies that target OXPHOS in T H 17-driven diseases.
Author Correction: Leveraging genomic diversity for discovery in an electronic health record linked biobank: the UCLA ATLAS Community Health Initiative
Authors: Ruth Johnson, Yi Ding, Vidhya Venkateswaran, Arjun Bhattacharya, Kristin Boulier, Alec Chiu, Sergey Knyazev, Tommer Schwarz, Malika Freund, Lingyu Zhan, Kathryn S. Burch, Christa Caggiano, Brian Hill, Nadav Rakocz, Brunilda Balliu, Christopher T. Denny, Jae Hoon Sul, Noah Zaitlen, Valerie A. Arboleda, Eran Halperin, Sriram Sankararaman, Manish J. Butte, Clara Lajonchere, Daniel H. Geschwind, Bogdan Pasaniuc
Journal: Genome Medicine (2022)
SIRPα-Fc fusion protein IMM01 exhibits dual anti-tumor activities by targeting CD47/SIRPα signal pathway via blocking the “don’t eat me” signal and activating the “eat me” signal
Authors: Jifeng Yu, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Wei Zhang, Li Zhang, Gui Zhao, Xiaoping Tu, Liang Peng, Sijin Liu, Xing Bai, Yongping Song, Zhongxing Jiang, Ruliang Zhang, Wenzhi Tian
Journal: Journal of Hematology & Oncology (2022)

A novel recombinant SIRPα-Fc fusion protein, IMM01, was constructed and produced using an in-house developed CHO-K1 cell expression system, and the anti-tumor mechanism of IMM01 targeting the CD47-SIRPα pathway was explored. The phagocytosis and in vitro anti-tumor activity of IMM01 were evaluated by antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC) assays. In vivo mouse tumor model studies were used to explore therapeutic efficacy as well as the mechanism of action. An in vitro binding assay revealed that IMM01 has a strong binding affinity to CD47 with an EC50 of 0.4967 nM. IMM01 can induce strong ADCP and moderate ADCC, but not CDC. IMM01-induced strong phagocytosis against tumor cells was attributed to dual activities of blocking the "don't eat me" signal and activating the "eat me" signal, and IMM01 exhibits strong and robust in vivo anti-tumor activities either as monotherapy on hematological malignancies, or in combination therapy with PD-L1 monoclonal antibody (mAb), PD-1 mAb, and HER-2 mAb on solid tumors. Finally, IMM01 demonstrated a favorable safety profile with no human RBC binding activity or hemagglutination induction. IMM01 inhibits the growth of tumor cells by the following three possible mechanisms: (1) directly activating macrophages to phagocytize tumor cells; (2) activated macrophages degrade phagocytized tumor cells and present tumor antigens to T cells through MHC molecules to activate T cells; (3) activated macrophages can convert "cold tumors" into "hot tumors" and increase the infiltration of immune cells through chemotaxis by secreting some cytokines and chemokines.
Abstract 15734: Intersection of Atrial Fibrillation and Heart Failure With Mildly Reduced and Preserved Ejection Fraction in &gt;400,000 Participants in the Get With the Guidelines® Heart Failure Registry
Authors: Ravi B Patel, Stephen J Greene, Haolin Xu, Brooke Alhanti, Pamela Peterson, Clyde W Yancy, Jonathan P Piccini, Gregg C Fonarow, Muthiah Vaduganathan
Journal: Circulation (2022)

Introduction: Atrial fibrillation or flutter (AF) and heart failure (HF) frequently coexist, yet few studies have examined longitudinal trends or post-discharge outcomes in this disease intersection. Methods: We evaluated 429,464 participants hospitalized for HF and left ventricular ejection fraction &gt;40% across 644 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry from January 2014 to December 2020. We compared clinical profiles among those with and without AF (defined by medical history or occurring at presentation or during hospitalization). We additionally examined 12-month post-discharge death and all-cause/cause-specific readmissions among 79,895 participants ≥65 years discharged alive with linked Centers for Medicare &amp; Medicaid Services inpatient files and Parts A, B, and D Fee-for-Service eligibility. Results: Prevalence of AF increased from 48.5% in Q1 2014 to 52.1% in Q4 2020 among the 76,886 patients with HF with mildly reduced ejection fraction (HFmrEF; 41-49%) and increased from 49.7% to 50.1% among the 352,578 patients with HF with preserved ejection fraction (HFpEF; ≥50%); both P-trend&lt;0.001. Among those with AF, 28% had a history of AF but were not actively in AF during hospitalization, while 11% had newly-detected AF at time of hospitalization. Median heart rate among those with AF was 80 (69-95)bpm at admission and 75 (66-86)bpm at discharge. Patients with AF faced higher 12-month rates of death (35% vs. 29%) and readmission for HF (30% vs. 27%), stroke (2.1% vs. 1.7%), bleeding (6% vs. 5%), and AF (5% vs. 2%). These associations persisted after adjustment for sociodemographic and clinical risk factors ( Figure ). Conclusions: Prevalence of AF is rising among patients hospitalized with HFmrEF and HFpEF. AF is independently associated with increased post-discharge risks of death and a broad range of clinical events requiring rehospitalization.
Universal clinical Parkinson’s disease axes identify a major influence of neuroinflammation
Authors: Cynthia Sandor, Stephanie Millin, Andrew Dahl, Ann-Kathrin Schalkamp, Michael Lawton, Leon Hubbard, Nabila Rahman, Nigel Williams, Yoav Ben-Shlomo, Donald G. Grosset, Michele T. Hu, Jonathan Marchini, Caleb Webber
Journal: Genome Medicine (2022)

Abstract Background There is large individual variation in both clinical presentation and progression between Parkinson’s disease patients. Generation of deeply and longitudinally phenotyped patient cohorts has enormous potential to identify disease subtypes for prognosis and therapeutic targeting. Methods Replicating across three large Parkinson’s cohorts (Oxford Discovery cohort ( n = 842)/Tracking UK Parkinson’s study ( n = 1807) and Parkinson’s Progression Markers Initiative ( n = 472)) with clinical observational measures collected longitudinally over 5–10 years, we developed a Bayesian multiple phenotypes mixed model incorporating genetic relationships between individuals able to explain many diverse clinical measurements as a smaller number of continuous underlying factors (“phenotypic axes”). Results When applied to disease severity at diagnosis, the most influential of three phenotypic axes “Axis 1” was characterised by severe non-tremor motor phenotype, anxiety and depression at diagnosis, accompanied by faster progression in cognitive function measures. Axis 1 was associated with increased genetic risk of Alzheimer’s disease and reduced CSF Aβ1-42 levels. As observed previously for Alzheimer’s disease genetic risk, and in contrast to Parkinson’s disease genetic risk, the loci influencing Axis 1 were associated with microglia-expressed genes implicating neuroinflammation. When applied to measures of disease progression for each individual, integration of Alzheimer’s disease genetic loci haplotypes improved the accuracy of progression modelling, while integrating Parkinson’s disease genetics did not. Conclusions We identify universal axes of Parkinson’s disease phenotypic variation which reveal that Parkinson’s patients with high concomitant genetic risk for Alzheimer’s disease are more likely to present with severe motor and non-motor features at baseline and progress more rapidly to early dementia.
Protein kinase Cι mediates immunosuppression in lung adenocarcinoma
Authors: Ning Yin, Yi Liu, Capella Weems, Barath Shreeder, Yanyan Lou, Keith L. Knutson, Nicole R. Murray, Alan P. Fields
Journal: Science Translational Medicine (2022)

Lung adenocarcinoma (LUAD) is the most prevalent form of non–small cell lung cancer (NSCLC) and a leading cause of cancer death. Immune checkpoint inhibitors (ICIs) of programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) signaling induce tumor regressions in a subset of LUAD, but many LUAD tumors exhibit resistance to ICI therapy. Here, we identified Prkci as a major determinant of response to ICI in a syngeneic mouse model of oncogenic mutant Kras / Trp53 loss (KP)–driven LUAD. Protein kinase Cι (PKCι)–dependent KP tumors exhibited resistance to anti–PD-1 antibody therapy (α-PD-1), whereas KP tumors in which Prkci was genetically deleted (KPI tumors) were highly responsive. Prkci- dependent resistance to α-PD-1 was characterized by enhanced infiltration of myeloid-derived suppressor cells (MDSCs) and decreased infiltration of CD8 + T cells in response to α-PD-1. Mechanistically, Prkci regulated YAP1-dependent expression of Cxcl5 , which served to attract MDSCs to KP tumors. The PKCι inhibitor auranofin inhibited KP tumor growth and sensitized these tumors to α-PD-1, whereas expression of either Prkci or its downstream effector Cxcl5 in KPI tumors induced intratumoral infiltration of MDSCs and resistance to α-PD-1. PRKCI expression in tumors of patients with LUAD correlated with genomic signatures indicative of high YAP1-mediated transcription, elevated MDSC infiltration and low CD8 + T cell infiltration, and with elevated CXCL5 / 6 expression. Last, PKCι-YAP1 signaling was a biomarker associated with poor response to ICI in patients with LUAD. Our data indicate that immunosuppressive PKCι-YAP1-CXCL5 signaling is a key determinant of response to ICI, and pharmacologic inhibition of PKCι may improve therapeutic response to ICI in patients with LUAD.
Diet-derived metabolites and mucus link the gut microbiome to fever after cytotoxic cancer treatment
Authors: Zaker I. Schwabkey, Diana H. Wiesnoski, Chia-Chi Chang, Wen-Bin Tsai, Dung Pham, Saira S. Ahmed, Tomo Hayase, Miriam R. Ortega Turrubiates, Rawan K. El-Himri, Christopher A. Sanchez, Eiko Hayase, Annette C. Frenk Oquendo, Takahiko Miyama, Taylor M. Halsey, Brooke E. Heckel, Alexandria N. Brown, Yimei Jin, Mathilde Raybaud, Rishika Prasad, Ivonne Flores, Lauren McDaniel, Valerie Chapa, Philip L. Lorenzi, Marc O. Warmoes, Lin Tan, Alton G. Swennes, Stephanie Fowler, Margaret Conner, Kevin McHugh, Tyler Graf, Vanessa B. Jensen, Christine B. Peterson, Kim-Anh Do, Liangliang Zhang, Yushu Shi, Yinghong Wang, Jessica R. Galloway-Pena, Pablo C. Okhuysen, Carrie R. Daniel-MacDougall, Yusuke Shono, Marina Burgos da Silva, Jonathan U. Peled, Marcel R.M. van den Brink, Nadim Ajami, Jennifer A. Wargo, Pavan Reddy, Raphael H. Valdivia, Lauren Davey, Gabriela Rondon, Samer A. Srour, Rohtesh S. Mehta, Amin M. Alousi, Elizabeth J. Shpall, Richard E. Champlin, Samuel A. Shelburne, Jeffrey J. Molldrem, Mohamed A. Jamal, Jennifer L. Karmouch, Robert R. Jenq
Journal: Science Translational Medicine (2022)

Not all patients with cancer and severe neutropenia develop fever, and the fecal microbiome may play a role. In a single-center study of patients undergoing hematopoietic cell transplant ( n = 119), the fecal microbiome was characterized at onset of severe neutropenia. A total of 63 patients (53%) developed a subsequent fever, and their fecal microbiome displayed increased relative abundances of Akkermansia muciniphila , a species of mucin-degrading bacteria ( P = 0.006, corrected for multiple comparisons). Two therapies that induce neutropenia, irradiation and melphalan, similarly expanded A. muciniphila and additionally thinned the colonic mucus layer in mice. Caloric restriction of unirradiated mice also expanded A. muciniphila and thinned the colonic mucus layer. Antibiotic treatment to eradicate A. muciniphila before caloric restriction preserved colonic mucus, whereas A. muciniphila reintroduction restored mucus thinning. Caloric restriction of unirradiated mice raised colonic luminal pH and reduced acetate, propionate, and butyrate. Culturing A. muciniphila in vitro with propionate reduced utilization of mucin as well as of fucose. Treating irradiated mice with an antibiotic targeting A. muciniphila or propionate preserved the mucus layer, suppressed translocation of flagellin, reduced inflammatory cytokines in the colon, and improved thermoregulation. These results suggest that diet, metabolites, and colonic mucus link the microbiome to neutropenic fever and may guide future microbiome-based preventive strategies.
APOE ε4 genotype, amyloid-β, and sex interact to predict tau in regions of high APOE mRNA expression
Authors: Aylin Dincer, Charles D. Chen, Nicole S. McKay, Lauren N. Koenig, Austin McCullough, Shaney Flores, Sarah J. Keefe, Stephanie A. Schultz, Rebecca L. Feldman, Nelly Joseph-Mathurin, Russ C. Hornbeck, Carlos Cruchaga, Suzanne E. Schindler, David M. Holtzman, John C. Morris, Anne M. Fagan, Tammie L.S. Benzinger, Brian A. Gordon
Journal: Science Translational Medicine (2022)

The apolipoprotein E ( APOE ) ε4 allele is strongly linked with cerebral β-amyloidosis, but its relationship with tauopathy is less established. We investigated the relationship between APOE ε4 carrier status, regional amyloid-β (Aβ), magnetic resonance imaging (MRI) volumetrics, tau positron emission tomography (PET), APOE messenger RNA (mRNA) expression maps, and cerebrospinal fluid phosphorylated tau (CSF ptau 181 ). Three hundred fifty participants underwent imaging, and 270 had ptau 181 . We used computational models to evaluate the main effect of APOE ε4 carrier status on regional neuroimaging values and then the interaction of ε4 status and global Aβ on regional tau PET and brain volumes as well as CSF ptau 181 . Separately, we also examined the additional interactive influence of sex. We found that, for the same degree of Aβ burden, APOE ε4 carriers showed greater tau PET signal relative to noncarriers in temporal regions, but no interaction was present for MRI volumes or CSF ptau 181 . This potentiation of tau aggregation irrespective of sex occurred in brain regions with high APOE mRNA expression, suggesting local vulnerabilities to tauopathy. There were greater effects of APOE genotype in females, although the interactive sex effects did not strongly mirror mRNA expression. Pathology is not homogeneously expressed throughout the brain but mirrors underlying biological patterns such as gene expression.